• Intracranial pressure (ICP) + induced hypertension [ Time Frame: within 5 days after ictus ]
  Measuring changes in ICP after induced hypertension
• Partial brain tissue oxygenation (PbtO2) + induced hypertension [ Time Frame: within 5 days after ictus ]
  Measuring changes in ICP after induced hypertension
• Mean flow index (Mxa) + hyper- and hypocapnia [ Time Frame: within 5 days after ictus, for 10 minutes after steady state ]
  Measuring during induction of hyper- and hypocapnia
• Intracranial pressure (ICP) + hyper- and hypocapnia [ Time Frame: within 5 days after ictus, for 10 minutes after steady state ]
  Measuring during induction of hyper- and hypocapnia
• Partial brain tissue oxygenation (PbtO2) + hyper- and hypocapnia [ Time Frame: within 5 days after ictus, for 10 minutes after steady state ]
  Measuring during induction of hyper- and hypocapnia
• Mean flow index (Mxa) + hyper- and hypoxia [ Time Frame: within 5 days after ictus, for 10 minutes after steady state ]
  Measuring during induction of hyper- and hypoxia
• Intracranial pressure (ICP) + hyper- and hypoxia [ Time Frame: within 5 days after ictus, for 10 minutes after steady state ]
  Measuring during induction of hyper- and hypoxia
• Partial brain tissue oxygenation (PbtO2) + hyper- and hypoxia [ Time Frame: within 5 days after ictus, for 10 minutes after steady state ]
  Measuring during induction of hyper- and hypoxia

The purpose is, in patients with aneurysmal subarachnoid haemorrhage in the early phase after ictus, to examine the following:

1. The effect of spontaneous and induced changes on the brain's static and dynamic autoregulation calculated by transcranial Doppler (TCD), ICP and MAP (primary purposes) and ICP and PbtO2;
2. The effect of mild hyper- and hypocapnia as well as of mild hyper- and hypoxia on the brain's static and dynamic autoregulation, ICP and PbtO2;
3. The relationship between brain autoregulation, mild hyper- and hypocapnia, as well as of mild hyper- and hypoxia and metabolism in microdialysate on the one hand and the occurrence of DCI during hospitalization and poor neurological outcome one year after ictus on the other.

Spontaneous aneurysm subarachnoid hemorrhage (SAH) occurs annually in approximately 400 people in Denmark. SAH is most commonly seen in younger (median age 56 years) and women (71%), have a high mortality (21-44%) and result in a poor neurological outcome in about 50% of patients. Due to the relatively young patient population and high mortality and morbidity, SAH in the population causes the same number of lost working years as blood clots in the brain.

The occurrence of complications like hydrocephalus and re-bleeding can be minimized by rapid external ventricular drainage and aneurysm closure, and so-called delayed cerebral ischaemia (DCI) is currently considered to be the most frequent serious complication of SAH. DCI occurs in 20-30% of patients, most often within the first 14 days, is characterized by a reduction in consciousness or focal neurological deficit lasting at least one hour without any other underlying cause and is associated with a significantly increased risk of a poor outcome. The cause and treatment of DCI is controversial, and the previous hypothesis of vasospasm as the sole contributor is currently supplemented by a broader focus on several other mechanisms, including the brain's blood supply and its regulation.

The brain's blood supply (CBF) is kept relatively constant in healthy by changing cardiac diameter and thus the cerebrovascular resistance (CVR) during changes in brain perfusion pressure (CPP, measured as mean arterial pressure (MAP) minus intracranial pressure (ICP)) within certain limits. This mechanism is known as cerebral autoregulation. Outside these limits, respectively. decreases and increases CBF, with the consequent risk of hypoperfusion/ischemia and hyperperfusion/vasogenic edema with prolonged changes.

Weakened autoregulation, i.e. that CBF varies passively with CPP also within the normal autoregulation limits, is described in e.g. traumatic brain injury (TBI), ischemic stroke, acute liver failure and meningitis, with complete or partial restoration of autoregulation by hyperventilation (mild hypocapnia). SAH also describes impaired autoregulation with varying association with disease severity, DCI and outcome. It is not known whether mild hypocapnia restores autoregulation in patients with SAH, whereas animal experimental studies suggest this.

Reduced intracerebral oxygenation (PbtO2) is associated with a worse outcome after SAH. Cerebral microdialysis measures the concentration of certain metabolites in the brain and can provide an insight into whether metabolic activity is affected by oxygen deficiency, and so-called anaerobic combustion occurs. Microdialysis measurements with elevated lactate concentration, which is a metabolic product, among other things. Anaerobic combustion appears to occur prior to clinical signs of DCI, as well as during the DCI episodes, decreasing PbtO2. It is possible that these findings could be due to a condition of impaired autoregulation and too low perfusion pressure to meet brain metabolic needs, but this has not previously been elucidated. It is also unknown if it is possible to improve brain metabolism by increasing the brain's perfusion pressure.

The purpose of this study is therefore to investigate brain autoregulation in patients with SAH.

• Other: Hypertension

  Hypertension is induced by an infusion of noradrenaline within acceptable limits Baseline recording (10 minutes) is performed. MAP gradually increases in steps of 5-10 mmHg during ongoing TCD. When the desired maximum MAP is reached, measurement is made at steady state (10 minutes).

  Noradrenaline infusion is stopped. When MAP is stabilized, new baseline is measured for 10 minutes.

• Other: Hyper- and hypoxia
  The mechanical ventilator is adjusted to mild hypoxia, normoxia and mild hyperoxia. Measurements are made for 10 minutes at normoxia and after steady state is reached, respectively. hyperoxia and hypoxia. Oxygenation is controlled by arterial blood gas before and during steady state.
• Other: Hyper- and hypocapnia
  The mechanical ventilator is adjusted to a delta PaCO2 on the ventilator for both hypocapnia and hypercapnia. Measurements are made for 10 minutes at normocapnia and after steady state is reached, respectively. hyper- and hypocapnia.

• Kurian MA, Li Y, Zhen J, Meyer E, Hai N, Christen HJ, Hoffmann GF, Jardine P, von Moers A, Mordekar SR, O'Callaghan F, Wassmer E, Wraige E, Dietrich C, Lewis T, Hyland K, Heales S Jr, Sanger T, Gissen P, Assmann BE, Reith ME, Maher ER. Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. Lancet Neurol. 2011 Jan;10(1):54-62. doi: 10.1016/S1474-4422(10)70269-6. Epub 2010 Nov 25.
• Olsen MH, Orre M, Leisner ACW, Rasmussen R, Bache S, Welling KL, Eskesen V, Møller K. Delayed cerebral ischaemia in patients with aneurysmal subarachnoid haemorrhage: Functional outcome and long-term mortality. Acta Anaesthesiol Scand. 2019 Oct;63(9):1191-1199. doi: 10.1111/aas.13412. Epub 2019 Jun 7.
• van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007 Jan 27;369(9558):306-18. Review.
• Brathwaite S, Macdonald RL. Current management of delayed cerebral ischemia: update from results of recent clinical trials. Transl Stroke Res. 2014 Apr;5(2):207-26. doi: 10.1007/s12975-013-0316-8. Epub 2013 Dec 13. Review.
• Schmidt JM, Wartenberg KE, Fernandez A, Claassen J, Rincon F, Ostapkovich ND, Badjatia N, Parra A, Connolly ES, Mayer SA. Frequency and clinical impact of asymptomatic cerebral infarction due to vasospasm after subarachnoid hemorrhage. J Neurosurg. 2008 Dec;109(6):1052-9. doi: 10.3171/JNS.2008.109.12.1052.
• Dankbaar JW, Slooter AJ, Rinkel GJ, Schaaf IC. Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review. Crit Care. 2010;14(1):R23. doi: 10.1186/cc8886. Epub 2010 Feb 22. Review.
• Roos YB, de Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. J Neurol Neurosurg Psychiatry. 2000 Mar;68(3):337-41.
• Dorhout Mees SM, Kerr RS, Rinkel GJ, Algra A, Molyneux AJ. Occurrence and impact of delayed cerebral ischemia after coiling and after clipping in the International Subarachnoid Aneurysm Trial (ISAT). J Neurol. 2012 Apr;259(4):679-83. doi: 10.1007/s00415-011-6243-2. Epub 2011 Sep 24.
• Budohoski KP, Czosnyka M, Kirkpatrick PJ, Smielewski P, Steiner LA, Pickard JD. Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage. Nat Rev Neurol. 2013 Mar;9(3):152-63. doi: 10.1038/nrneurol.2013.11. Epub 2013 Feb 19. Review.
• Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014 Jan;10(1):44-58. doi: 10.1038/nrneurol.2013.246. Epub 2013 Dec 10. Review.
• LASSEN NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev. 1959 Apr;39(2):183-238.
• Berg, R.M.G., Pedersen, M., Møller, K.: Static cerebral blood flow autoregulation in humans. Curr. Hypertens. Rev. 5, 140-157 (2009).
• Czosnyka M, Smielewski P, Piechnik S, Steiner LA, Pickard JD. Cerebral autoregulation following head injury. J Neurosurg. 2001 Nov;95(5):756-63.
• Eames PJ, Blake MJ, Dawson SL, Panerai RB, Potter JF. Dynamic cerebral autoregulation and beat to beat blood pressure control are impaired in acute ischaemic stroke. J Neurol Neurosurg Psychiatry. 2002 Apr;72(4):467-72.
• Strauss G, Hansen BA, Knudsen GM, Larsen FS. Hyperventilation restores cerebral blood flow autoregulation in patients with acute liver failure. J Hepatol. 1998 Feb;28(2):199-203.
• Møller K, Skinhøj P, Knudsen GM, Larsen FS. Effect of short-term hyperventilation on cerebral blood flow autoregulation in patients with acute bacterial meningitis. Stroke. 2000 May;31(5):1116-22.
• Otite F, Mink S, Tan CO, Puri A, Zamani AA, Mehregan A, Chou S, Orzell S, Purkayastha S, Du R, Sorond FA. Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage. Stroke. 2014 Mar;45(3):677-82. doi: 10.1161/STROKEAHA.113.002630. Epub 2014 Jan 14.
• Budohoski KP, Czosnyka M, Kirkpatrick PJ, Reinhard M, Varsos GV, Kasprowicz M, Ząbek M, Pickard JD, Smielewski P. Bilateral failure of cerebral autoregulation is related to unfavorable outcome after subarachnoid hemorrhage. Neurocrit Care. 2015 Feb;22(1):65-73. doi: 10.1007/s12028-014-0032-6.
• Ma X, Willumsen L, Hauerberg J, Pedersen DB, Juhler M. Effects of graded hyperventilation on cerebral blood flow autoregulation in experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2000 Apr;20(4):718-25.
• Ramakrishna R, Stiefel M, Udoetuk J, Spiotta A, Levine JM, Kofke WA, Zager E, Yang W, Leroux P. Brain oxygen tension and outcome in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 2008 Dec;109(6):1075-82. doi: 10.3171/JNS.2008.109.12.1075. Erratum in: J Neurosurg. 2009 Mar;110(3):613. Udoteuk, Joshua [corrected to Udoetuk, Joshua].
• Skjøth-Rasmussen J, Schulz M, Kristensen SR, Bjerre P. Delayed neurological deficits detected by an ischemic pattern in the extracellular cerebral metabolites in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 2004 Jan;100(1):8-15.
• Roh DJ, Morris NA, Claassen J. Intracranial Multimodality Monitoring for Delayed Cerebral Ischemia. J Clin Neurophysiol. 2016 Jun;33(3):241-9. doi: 10.1097/WNP.0000000000000277. Review.

Inclusion Criteria, patients:

• Admittance to neurointensive care unit, Rigshospitalet
• Age ≥ 18 years old
• Aneurysmal subarachnoid haemorrhage
• Clinical indication for placement of an external ventricular drain
• Measurements can be done within 3 days of ictus
• Closest relatives understand written and spoken danish

Exclusion Criteria, patients:

• No aneurysm identified
• Conservative og failed treatment of aneurysm
• Pupils dilated and do not react to light
• Incarceration before inclusion
• Expected death within 48 hours
• Acute or chronic diseases associated with impaired autoregulation
• Severe chronic lung failure with a PaCO2 > 6.5 kPa or PaO2 < 8 kPa.

Inclusion Criteria, healthy subjects:

• Age ≥ 18 years old;
• Understands written and spoken danish
• Oral and written consent
• No medication expect hay fever medications
• Alcohol consumption within the limits from the danish health care board
• Healthy without previous or current cerebrovascular diseases
• Insonation is possible from the middle cerebral artery